Small molecule modulators of the cold and menthol receptor trpm8

ABSTRACT

The present invention relates to the use of compounds which are capable of producing a cooling sensation when they are brought into contact with the human body. In particular, the present invention relates to the use of compounds modulating TRPM8, and optionally to the use of compounds selectively exhibiting agonist activity at the TRPM8 channel. Such compounds have applications in many fields, particularly in oral and personal hygiene products and foodstuffs, but also in pharmaceutical composition products, cosmetics, textile products and packaging products. The present invention further relates to products containing such compounds and to the medical use of such compounds.

SUBJECT OF THE INVENTION

The present invention relates to the use of compounds which are capableof producing a cooling sensation when they are brought into contact withthe human body. In particular, the present invention relates to the useof compounds modulating TRPM8, and optionally to the use of compoundsselectively exhibiting agonist activity at the TRPM8 channel. Suchcompounds have applications in many fields, particularly in oral andpersonal hygiene products and foodstuffs, but also in pharmaceuticalcomposition products, cosmetics, textile products and packagingproducts. The present invention further relates to products containingsuch compounds and to the medical use of such compounds.

BACKGROUND OF THE INVENTION

The transient receptor potential (TRP) ion channel family is a group ofion channels located mostly in the plasma membrane of numerous human andanimal cell types. There are about 28 TRP channels that share somestructural similarity to each other. Many of these channels mediate avariety of sensations like the sensations of pain, hotness, warmth orcoldness, different kinds of tastes, pressure and vision. In the body,some TRP channels are thought to be involved in thermosensation and tobe used in animals to sense hot or cold. Some TRP channels are activatedby the pungent ingredients of spices like garlic, chilli pepper, wasabi;others are activated by menthol, camphor, peppermint, and coolingagents; yet others are activated by drugs like cannabinoids, e.g.marijuana. Some act as sensors of cellular stress such as osmoticpressure, volume, stretch, and vibration.

Six protein families are comprised by the mammalian TRP superfamily: theclassic TRPs (TRPCs), the vanilloid receptor TRPs (TRPVs), themelastatin or long TRPs (TRPMs), the mucolipins (TRPMLs), thepolycystins (TRPPs), and ankyrin transmembrane protein 1 (ANKTM1,TRPA1). With the exception of some polycystins, TRPs are generallyassumed to have six transmembrane domains. The TRP channels are a familyof ion channel proteins that mediate ion influx of Na⁺ and Ca²⁺ and, inseveral cases, Mg²⁺ and other divalent cations. Since TRPs areintimately linked with intracellular Ca²⁺ signaling, they are implicatedin the control of cell cycle progression, cell migration, and programmedcell death.

The TRPM subfamily comprises eight members, including the cold andmenthol receptor TRPM8, also designated as TRP melastatin 8, cold andmenthol receptor 1 (CMR1) or transient receptor potential cation channelsubfamily M member 8. In 2002, using divergent approaches, twoscientific groups simultaneously identified and described TRPM8 (McKemyD D et al., Nature 2002, 416(6876):52-58; Peier A M et al., Cell 2002,108(5):705-15). The channel is expressed, e.g., in small-diameterprimary sensory neurones, where it presumably functions as athermosensor. TRPM8 consists of six putative transmembrane spanningsegments, a pore-forming loop and intracellularly located NH₂ and COOHtermini. Assembly of channel subunits as tetramers results in theformation of cation-selective channels that permeate calcium ions. TRPM8is involved in the detection of sensations such as coolness triggered,inter alia, by cooling agents and/or by cold (i.e. temperatures rangingfrom about 8° C. to about 28° C.).

Cooling agents are used extensively by flavor and fragrance suppliers inorder to evoke associations with freshness and cleanliness. Hence, overthe last 30 years a considerable number of compounds have beensynthesized and evaluated for the physiological sensation of “cooling”.For instance, the international patent application WO 2010/017609discloses the use of the ingredients of Mentha and Eucalyptus oil asantiperspirants, the ingredients presumably acting as TRPM8 agonists.Furthermore, menthol, a cyclic terpene alcohol found in leaves of thegenus Mentha, is used in a wide range of products, such asconfectionary, candy, toothpastes, vaporubs, and aromatherapyinhalations. When applied at low concentrations to the skin or the oralmucosa, menthol elicits a pleasant cool sensation, while higher dosescan cause burning, irritation, and pain.

It is known in the art that menthol can act as natural modulator ofTRPM8 (McKemy D D et al., Nature 2002, 416(6876):52-58; Peier A M etal., Cell 2002, 108(5):705-15; McKemy D D, Molecular Pain 2005, 1:16).Upon activation, a signal transduction cascade is mediated by TRPM8,producing the perception of cold in the nervous system. For instance,activation of TRPM8 can induce an increase of intracellular calcium ionsin cold-sensitive neurones. This calcium influx subsequently produces aninward current that provokes cold sensing.

In addition to menthol, a number of further cooling agents, includingicilin (also designated as AG-3-5), Cool-actP, Cooling Agent 10,FrescolatMGA, FrescolatML, geraniol, hydroxycitronellal, linalool,PMD38, WS-3, and WS-23 are known in the art to activate TRPM8 in vitro(McKemy D D et al., Nature 2002, 416(6876):52-58; Weil A et al., Mol.Pharmacol. 2005, 68(2):518-27; Behrendt H J et al., Br. J. Pharmacol.2004, 141(4):737-45). Of these icilin, was first identified as asuper-cooling agent in the early 1980s and bears little resemblance tomenthol structurally (WO 2004/026840).

A number of methanol derivatives or other cooling agents which mayexhibit a similar action at TRPM8 are known in the art. For instance,the international patent application WO 2010/026094 relates tomodulators of TRPM8, to a method of modulating the TRPM8 channel, to theuse of the modulators for induction of cold sensation and to the objectsand means produced using said modulators. High concentrations of mentholcan trigger other ion channels (e.g. TRPA1), presumably leading to theseunpleasant sensations through activation of nociceptive sensory neurons(see e.g. review by McKemy D D, Mol. Pain. 2005, 1:16). In additionmenthol has a typical flavour and aroma which sometimes isdisadvantageous for industrial applications in the food and cosmeticindustry. Hence, there is a need for compounds which selectivelymodulate TRPM8, e.g. compounds which exhibit distinct activationconcentrations at TRPM8 and TRPA1.

TRPA1 is a member of the TRPA branch of the TRP ion channel gene family.TRPA1 was identified as a potential mediator of noxious cold stimuli innociceptive sensory neurons. Moreover, recent studies found evidencethat TRPA1 is involved in sensory neural responses to mustard oil,allicin, and other chemical irritants (Jordt S E et al., Nature 2004,427(6971):260-65; Bandell M et al., Neuron. 2004, 41(6):849-57). Hence,TRPA1 channels respond to a multitude of irritants with diverse originsand chemical structures, leading to, amongst others, sensations of pain,coughing, apnea, and lachrymation.

Some of the above-mentioned cooling agents have cooling effects at leastto some extents, but may be insufficient and unsatisfactory in theretainability of the cooling effect. Hence, there is a strong demand inthe art for providing cooling agents that have an improved sensorystimulating effect. Furthermore, some of the cooling agents known in theart may be insufficient with regard to their efficacy, their period ofaction, their scent, their taste, their solubility, and/or theirvolatility, and/or may cause irritation of the mucous membranes, itchingof skin, tearing and/or the urge to cough. Accordingly, there is a needfor alternative cooling agents that may overcome one or more of thesedrawbacks.

OBJECT AND SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds that modulate theTRPM8 channel activity. In certain embodiments of the invention, suchcompounds exhibit agonist activity at the TRPM8 channel. In certainembodiments of the invention, such compounds exhibit partial agonistactivity at the TRPM8 channel. In certain embodiments of the invention,such compounds exhibit selective agonist activity at the TRPM8 channel.In certain embodiments of the invention, such compounds exhibitantagonistic activity at the TRPM8 channel. In certain embodiments ofthe invention, such compounds exhibit partial antagonistic activity atthe TRPM8 channel. In certain embodiments of the invention, suchcompounds exhibit selective antagonistic activity at the TRPM8 channel.

In certain embodiments of the invention, such compounds exhibit activityfor activating TRPM8 in a lower concentration range than needed foractivating TRPA1. In another embodiment, a compound of the inventionacts as a TRPM8 agonist, but not as a TRPA1 agonist. In anotherembodiment, a compound of the invention acts as a TRPM8 partial agonist,but not as a TRPA1 agonist.

It is a further object of the invention to provide compounds which areexcellent in evocation of cool and/or refreshing feeling or chilly andrefreshing feeling without giving undesirable stimulation, peculiarodor, stinging, pungent or burning sensations and/or bitter taste, andwhich are usable as cooling agents and/or sensory stimulation agents. Itis a further object of the invention to provide compounds whichselectively modulate the cold and menthol receptor TRPM8. It is also anobject of the invention to provide selective agonists of the cold andmenthol receptor TRPM8. It is a further object of the invention toprovide compounds which modulate the cold and menthol receptor TRPM8,but do not substantially trigger TRPA1, or at least to a lesser extent.

Also, the object of the invention is to provide cooling agentcompositions comprising one or more of said compounds. Further, theobject of the invention is to provide fragrance compositions, beverageor food products, cosmetic products, toiletry products, bathing agents,textile products, packaging products or pharmaceutical productscomprising one or more of said compounds.

These objectives as well as others which will become apparent from theensuing description are attained by the subject matter of theindependent claims. Some of the embodiments of the present invention aredefined by the subject matter of the dependent claims.

In one embodiment, the present invention relates to a product comprisinga compound that selectively modulates TRPM8, and wherein the product isselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product.

According to an optional embodiment, the compound exhibits selectiveagonist activity at TRPM8.

According to a further optional embodiment, the compound exhibitsactivity at TRPM8, which activity is at least three times or even atleast four times, greater than the activity of the compound at TRPA 1.

According to a further optional embodiment, in a functional cell basedassay the compound modulates the intracellular calcium level of humancells recombinantly expressing human TRPM8 at least four times moreefficient than that of human cells recombinantly expressing human TRPA1.

Optionally, the compound is selected from the group consisting ofCompounds I.1, II.1, III.1, IV.1, V.1, VI.1, and VII.1, the Compoundshaving the chemical structures as described hereinafter.

Optionally, the compound is selected from the group consisting ofCompounds I.2, II.2, III.2, IV.2, V.2, VI.2, and VII.2, the Compoundshaving the chemical structures as described hereinafter.

Optionally, the compound is selected from the group consisting ofCompounds I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, the Compoundshaving the following chemical structures:

Com- pound Chemical structure I.3

II.3

III.3

IV.3

V.3

VI.3

VII.3

In one further embodiment, the present invention relates to the use of acompound as defined in any of claims 1 to 6 and/or as describedhereinafter in a product selected from the group consisting of acosmetic product composition, a food product composition, a textileproduct, a pharmaceutical product composition, and a packaging product.

According to an optional embodiment, the cosmetic product composition isselected from the group consisting of an insect repellent composition,an oral hygiene composition, a skin care composition, and a hair carecomposition.

According to an optional embodiment, the food product composition isselected from the group consisting of ice cream, mousse, crème,beverages and confectionery.

According to an optional embodiment, the textile product is selectedfrom the group consisting of shirts, trousers, socks, towels, headgear,underwear and shoes.

According to an optional embodiment, the pharmaceutical productcomposition is selected from the group consisting of anticancermedicaments, medicaments for the treatment of bladder diseases, andmedicaments for the treatment of pain.

In one further embodiment, the present invention relates to a compoundas defined in any of claims 1 to 6 and/or as described hereinafter foruse in therapy.

In one further embodiment, the present invention relates to a compoundas defined in any of claims 1 to 6 and/or as described hereinafter foruse in the treatment of pain.

In one further embodiment, the present invention relates to a cosmeticuse of a compound as defined in any of claims 1 to 6 and/or as describedhereinafter as cooling agent.

In one further embodiment, the present invention relates to an in vitromethod of modulating the cold and menthol receptor TRPM8, wherein TRPM8is contacted with a compound as defined in any of claims 1 to 6 and/oras described hereinafter.

FIGURE LEGENDS

The accompanying drawings, which are incorporated and form part of thespecification, merely illustrate certain embodiments of the presentinvention. They are meant to serve to explain specific modes of thepresent invention to those of skilled in the art. In the drawings:

FIG. 1 depicts a comparison of the EC₅₀ value of Compound I.3 acting asactivator of TRPM8 with the EC₅₀ value of Compound I.3 acting asactivator of TRPA1, as well as the chemical structure of Compound I.3.EC₅₀ of Compound I.3 acting as activator of TRPM8 is about 2.01 μM. EC₅₀of Compound I.3 acting as activator of TRPA1 is about 72.42 μM. Hence,EC₅₀ of Compound I.3 acting as activator of TRPM8 is about 36 timeslower than EC₅₀ of Compound I.3 acting as activator of TRPA1. Theefficacy of Compound I.3 with respect to activation of TRPM8 has beenevaluated to be about 110.06% (compared to 20 μM menthol).

FIG. 2 depicts a comparison of the EC₅₀ value of Compound II.3 acting asactivator of TRPM8 with the EC₅₀ value of Compound II.3 acting asactivator of TRPA1, as well as the chemical structure of Compound II.3.EC₅₀ of Compound II.3 acting as activator of TRPM8 is about 8.01 μM.EC₅₀ of Compound II.3 acting as activator of TRPA1 is about 123.22 μM.Hence, EC₅₀ of Compound II.3 acting as activator of TRPM8 is about 15.4times lower than EC₅₀ of Compound II.3 acting as activator of TRPA1. Theefficacy of Compound II.3 with respect to activation of TRPM8 has beenevaluated to be about 46.59% (compared to 20 μM menthol).

FIG. 3 depicts a comparison of the EC₅₀ value of Compound III.3 actingas activator of TRPM8 with the EC₅₀ value of Compound III.3 acting asactivator of TRPA1, as well as the chemical structure of Compound III.3.EC₅₀ of Compound III.3 acting as activator of TRPM8 is about 5.27 μM.EC₅₀ of Compound III.3 acting as activator of TRPA1 is about 113.40 μM.Hence, EC₅₀ of Compound III.3 acting as activator of TRPM8 is about 21.5times lower than EC₅₀ of Compound III.3 acting as activator of TRPA1.The efficacy of Compound III.3 with respect to activation of TRPM8 hasbeen evaluated to be about 97.65% (compared to 20 μM menthol).

FIG. 4 depicts a comparison of the EC₅₀ value of Compound IV.3 acting asactivator of TRPM8 with the EC₅₀ value of Compound IV.3 acting asactivator of TRPA1, as well as the chemical structure of Compound IV.3.EC₅₀ of Compound IV.3 acting as activator of TRPM8 is about 4.12 μM.EC₅₀ of Compound IV.3 acting as activator of TRPA1 is about 117.89 μM.Hence, EC₅₀ of Compound IV.3 acting as activator of TRPM8 is about 28.6times lower than EC₅₀ of Compound IV.3 acting as activator of TRPA1. Theefficacy of Compound IV.3 with respect to activation of TRPM8 has beenevaluated to be about 34.14% (compared to 20 μM menthol).

FIG. 5 depicts a comparison of the EC₅₀ value of Compound V.3 acting asactivator of TRPM8 with the EC₅₀ value of Compound V.3 acting asactivator of TRPA1, as well as the chemical structure of Compound V.3.EC₅₀ of Compound V.3 acting as activator of TRPM8 is about 7.53 μM. EC₅₀of Compound V.3 acting as activator of TRPA1 is about 138.37 μM. Hence,EC₅₀ of Compound V.3 acting as activator of TRPM8 is about 18.4 timeslower than EC₅₀ of Compound V.3 acting as activator of TRPA1. Theefficacy of Compound V.3 with respect to activation of TRPM8 has beenevaluated to be about 70.90% (compared to 20 μM menthol).

FIG. 6 depicts a comparison of the EC₅₀ value of Compound VI.3 acting asactivator of TRPM8 with the EC₅₀ value of Compound VI.3 acting asactivator of TRPA1, as well as the chemical structure of Compound VI.3.EC₅₀ of Compound VI.3 acting as activator of TRPM8 is about 8.15 μM.EC₅₀ of Compound VI.3 acting as activator of TRPA1 is about 107.64 μM.Hence, EC₅₀ of Compound VI.3 acting as activator of TRPM8 is about 13.2times lower than EC₅₀ of Compound VI.3 acting as activator of TRPA1. Theefficacy of Compound VI.3 with respect to activation of TRPM8 has beenevaluated to be about 95.36% (compared to 20 μM menthol).

FIG. 7 depicts a comparison of the EC₅₀ value of Compound VII.3 actingas activator of TRPM8 with the EC₅₀ value of Compound VII.3 acting asactivator of TRPA1, as well as the chemical structure of Compound VII.3.EC₅₀ of Compound VII.3 acting as activator of TRPM8 is about 10.94 μM.EC₅₀ of Compound VII.3 acting as activator of TRPA1 is about 56.62 μM.Hence, EC₅₀ of Compound VII.3 acting as activator of TRPM8 is about 5.2times lower than EC₅₀ of Compound VII.3 acting as activator of TRPA1.The efficacy of Compound VII.3 with respect to activation of TRPM8 hasbeen evaluated to be about 45.12% (compared to 20 μM menthol).

DETAILED DESCRIPTION OF THE INVENTION

The present invention illustratively described in the following maysuitably be practiced in the absence of any element or elements,limitation or limitations, not specifically disclosed herein.

The present invention will be described with respect to particularembodiments and with reference to certain drawings but the invention isnot limited thereto but only by the claims. The drawings described areonly schematic and are non-limiting. In the drawings, the size of someof the elements may be exaggerated and not drawn on scale forillustrative purposes.

Where the term “comprising” is used in the present description andclaims, it does not exclude other elements or steps. For the purposes ofthe present invention, the term “consisting of” is considered to be apreferred embodiment of the term “comprising of”. If hereinafter a groupis defined to comprise at least a certain number of embodiments, this isalso to be understood to disclose a group which optionally consists onlyof these embodiments.

Where an indefinite or definite article is used when referring to asingular noun e.g. “a” or “an”, “the”, this includes a plural of thatnoun unless something else is specifically stated.

The term “about” in the context of the present invention denotes aninterval of accuracy that the person skilled in the art will understandto still ensure the technical effect of the feature in question. Theterm typically indicates deviation from the indicated numerical value of+10%, and optionally ±5%.

Furthermore, the terms first, second, third and the like in thedescription and in the claims, are used for distinguishing betweensimilar elements and not necessarily for describing a sequential orchronological order. It is to be understood that the terms so used areinterchangeable under appropriate circumstances and that the embodimentsof the invention described herein are capable of operation in othersequences than described or illustrated herein.

Further definitions of term will be given in the following in thecontext of which the terms are used.

Compounds

In one embodiment, the present invention relates to a compound havingthe following general formula (I):

or a pharmaceutically acceptable derivative thereof wherein:Q is selected from fused benzo or (5- or 6-membered)heteroaryl;each R₁ is independently selected from:

-   -   (a) -halo, —CN, —NO₂; or    -   (b) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (c) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (d) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (e) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (f) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, each        of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₅ groups; or    -   (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        a is an integer selected from 0, 1, 2 or 3;        R₂ is selected from ═O, ═NT₃, ═S, —OT₃, —OC(═O)T₃,        —OC(═O)N(T₁)(T₂), —OC(═O)OT₃, —ST₃, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂), —S(═O)OT₃, —S(═O)N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, or —N(T₃)S(═O)N(T₁)(T₂);        R₃ and R₄ are each independently selected from:    -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (d) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (f) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (g) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        E is selected from C(T₁)(T₂), O, S or NT₃;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₃, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which        is unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups;        the dashed line in the 6-membered ring denotes the presence or        absence of a bond; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (I.1):

or a pharmaceutically acceptable derivative thereof wherein:Q is selected from fused benzo or 6-membered heteroaryl;each R₁ is independently selected from:

-   -   (a) -halo, —CN, —NO₂; or    -   (b) —OT₃, —OC(═O)T₃; or    -   (c) —C(═O)T₃; or    -   (d) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃; or    -   (e) —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,        —(C₁-C₄)alkoxy, each of which is unsubstituted or substituted        with 1 or 2 independently selected R₅ groups;        a is an integer selected from 0, 1, or 2;        Y and E are each independently selected from O, S, or NT₃;        R₃ and R₄ are each independently selected from:    -   (a) —H; or    -   (b) —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,        —(C₁-C₄)alkoxy, each of which is unsubstituted or substituted        with 1 or 2 independently selected R₅ groups;    -   (c) -phenyl or -(5- or 6-membered)heteroaryl containing 1 or 2        atoms selected from the group consisting of O, N and S, each of        which is unsubstituted or substituted with 1 or 2 independently        selected R₆ groups;        the dashed line in the 6-membered ring denotes the presence or        absence of a bond;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₃ is independently —H or —(C₁-C₅)alkyl which is        unsubstituted or substituted with 1 or 2 independently selected        R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (I.2):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from —H; —OT₃, —ST₃, or —(C₁-C₃)alkyl, wherein T₃ isselected from —H or —(C₁-C₂)alkyl;R₃ is selected from -phenyl or -heteroaryl selected from the groupconsisting of pyridine, pyrazine, pyridazine and pyrimidine, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;R₄ is selected from —(C₁-C₃)alkyl, —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, or—(C₁-C₃)alkoxy; andR₆ is selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl, —(C₂)alkynyl, —OR₇,—SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,—N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or —S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein the fused benzo is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein the fused benzo is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein the fused benzo is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein the fused benzo is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is selected from —H; —Cl, —OH, —OCH₃,—SH, —SCH₃ or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein the fused benzo is substituted as follows:

wherein R₁ is selected from —H; —OH, —OCH₃, or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is -phenyl, which is unsubstituted orsubstituted with 1 or 2 independently selected groups selected from —H,—CH₃, —OH, —SH, —OCH₃, and —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is -phenyl, which is unsubstituted.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein R₄ is selected from —H, —CH₃, and —CH₂CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, wherein halo is Cl.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (II):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl or -(5- or 6-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₆ groups;R₂, each R₃ and each R₄ are each independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) ═O, —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (d) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (e) ═S, —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (f) ═NT₃, —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃,        —N(T₃)C(═O)OT₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃,        —N(T₃)S(═O)₂N(T₁)(T₂), —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (g) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;    -   wherein both R₄ can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups;        E is selected from C(T₁)(T₂), O, S or NT₃;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently is independently —H or        —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2        or 3 independently selected R₅ groups;        the dashed line denotes the presence or absence of a bond; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (II.1):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl or -(6-membered)heteroaryl, each of which isunsubstituted or substituted with 1, 2 or 3 independently selected R₆groups;R₂ and each R₄ are each independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃; or    -   (d) —C(═O)T₃; or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃; or    -   (f) —(C₁-C₅)alkyl, —(C₂-C₅)alkenyl, —(C₂-C₅)alkynyl,        —(C₁-C₅)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1 or 2 independently selected R₅ groups;        wherein both R₄ can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1 or 2 independently selected        R₅ groups; or        E is selected from O, S or NT₃;        each Y is independently selected from O, S or NT₃;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₃ is independently —H or —(C₁-C₅)alkyl which is        unsubstituted or substituted with 1 or 2 independently selected        R₅ groups;        the dashed line denotes the presence or absence of a bond; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (II.2):

or a pharmaceutically acceptable derivative thereof wherein:each R₁ is independently selected from —(C₁-C₂)alkyl, —(C₂)alkenyl,—(C₂)alkynyl, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo,—N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or—S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃; each halo isindependently selected from —F, —Cl, —Br, or —I;a is an integer selected from 1 or 2;each T₃ is independently selected from —H or —(C₁-C₂)alkyl;the dashed line denotes the presence or absence of a bond; andeach Y is independently selected from O, S or NT₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein a is 2 and the phenyl group comprising—(R₁)_(a) is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein a is 2 and the phenyl group comprising—(R₁)_(a) is substituted as follows:

wherein R₁ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein a=2 and each R₁ is independently selectedfrom —H; —OH, —Cl, —OCH₃, —SH, —SCH₃ or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein a=1 and R₁ is selected from —H; —OH, Cl,—OCH₃, —SH, —SCH₃ or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein a is 2 and the phenyl group comprising—(R₁)_(a) is substituted as follows:

wherein each R₁ is independently selected from —H; —OH, —OCH₃, —SH,—SCH₃, —Cl or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein each T₃ is independently selected from —H or—CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein the dashed line denotes the presence of abond.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, wherein each Y is O.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (III):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₆ groups;        R₂ is selected from ═O, ═NT₃, ═S, —OT₃, —OC(═O)T₃,        —OC(═O)N(T₁)(T₂), —OC(═O)OT₃, —ST₃, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂), —S(═O)OT₃, —S(═O)N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, or —N(T₃)S(═O)N(T₁)(T₂);        R₃ is selected from:    -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is substituted        with 1 or 2 independently selected R₄ groups; or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is substituted with 1 or 2        independently selected R₄ groups;        each R₄ is independently selected from:    -   (a) —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1 or 2 independently selected R₅ groups; or    -   (b) -phenyl, or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1 or 2 independently selected        R₆ groups;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        the dashed line denotes the presence or absence of a bond,        wherein E₁ is selected from C(T₃)₂, O, S or NT₃ if the bond is        absent, and E₁ is selected from CT₃, or N if the bond is        present;        E₂ is selected from C(T₃)₂, O, S or NT₃;        each T₁, T₂, and T₃ is independently is independently —H or        —(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2        or 3 independently selected R₅ groups; and each halo is        independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (III.1):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl, or -(5- or 6-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;Y is selected from O, S, or NT₃;R₄ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1 or 2 independently selected R₅ groups; or    -   (b) -phenyl, or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1 or 2 independently selected        R₆ groups;        E₁ is selected from CT₃, or N;        E₂ is selected from C(T₃)₂, O, S or NT₃;        E₃ is selected from C(T₃)₂, O, S or NT₃;        E₄ is selected from CT₃, or N;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —SR₇,        —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,        —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₃ is independently —H or —(C₁-C₅)alkyl which is        unsubstituted or substituted with 1 or 2 independently selected        R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (III.2):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from: -phenyl, or -heteroaryl selected from the groupconsisting of pyridine, pyrazine, pyridazine and pyrimidine, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;F₃ is selected from C(T₃)₂, O, S or NT₃;E₄ is selected from CT₃, or N;E₅ is selected from C(T₃)₂, O, or S;R₆ is selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl, —(C₂)alkynyl, —OR₇,—SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,—N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or —S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃;each T₃ is independently selected from —H or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is selected from —H, —CH₃, —OH, —SH, —OCH₃, or —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein E₃ is NT₃ and T₃ is as defined above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein E₄ is N.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein E₅ is S.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein E₃ is NT₃, E₄ is N and E₅ is S, and T₃ is asdefined above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₆ is selected from —H, —CH₃, —OH, —SH,—OCH₃, or —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is -phenyl, which is unsubstituted orsubstituted with 1 or 2 independently selected groups selected from —H,—CH₃, —OH, —SH, —OCH₃, —NH₂, —N(CH₃)₂ and —Cl.

In one embodiment, the present invention relates to a compound havingthe following general formula (IV):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₄ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₄ groups;        R₂ is selected from ═O, ═NT₃, ═S, —OT₃, —OC(═O)T₃,        —OC(═O)N(T₁)(T₂), —OC(═O)OT₃, —ST₃, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂), —S(═O)OT₃, —S(═O)N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, or —N(T₃)S(═O)N(T₁)(T₂);        R₃ is selected from:    -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₆ groups;        each R₄ is independently selected from:    -   (a) -halo, —CN, —NO₂; or    -   (b) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (c) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (d) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (e) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (f) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, each        of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₅ groups; or    -   (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        E₁ and E₂ are each independently selected from C(T₃)₂, O, S or        NT₃;        the dashed line denotes the presence or absence of a bond;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which        is unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In one embodiment, the present invention relates to a compound havingthe following general formula (IV.1):

or a pharmaceutically acceptable derivative thereof wherein:R₃ is selected from -phenyl, or -(6-membered)heteroaryl, each of whichis unsubstituted or substituted with 1 or 2 independently selected R₆groups;each R₄ is independently selected from:

-   -   (a) —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,        —(C₁-C₄)alkoxy, each of which is unsubstituted or substituted        with 1 or 2 independently selected R₅ groups;        or    -   (b) —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S,        -halo, —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)N(T₁)(T₂),        —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or —S(═O)₂R₇;        Y is selected from O, S, or NT₃;        E₁ and E₂ are each independently selected from C(T₃)₂, O, S or        NT₃;        each dashed line in the 6-membered ring independently denotes        the presence or absence of a bond, wherein E₃ is selected from        C(T₃)₂, or NT₃ if the adjacent bond is absent, and E₃ is        selected from CT₃, or N if the adjacent bond is present;        E₄ is selected from C(T₃)₂, or NT₃;        a is an integer selected from 1, 2 or 3;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₅)alkyl which        is unsubstituted or substituted with 1 or 2 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In one embodiment, the present invention relates to a compound havingthe following general formula (IV.2):

or a pharmaceutically acceptable derivative thereof wherein:R₃ is selected from: -phenyl, or -heteroaryl selected from the groupconsisting of pyridine, pyrazine, pyridazine and pyrimidine, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;R₄ is selected from: —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,—(C₁-C₄)alkoxy;E₁ is selected from O or S;Y is selected from O or S;each R₆ is independently selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl,—(C₂)alkynyl, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo,—N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or—S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃;each T₃ is independently selected from —H or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is:

wherein R₆ is defined as above and a is an integer selected from 1 or 2.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₃ is:

wherein R₆ is selected from —C(Cl)₃, —CH(Cl)₂, —CH₂(Cl), —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₄ is —(C₁-C₄)alkyl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein E₁ is S.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein Y is O.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein R₆ is -halo.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, wherein halo is Cl.

In one embodiment, the present invention relates to a compound havingthe following general formula (V):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₃ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, -(5- or        6-membered)heteroaryl or -(7- or 10-membered)heteroaryl, each of        which is unsubstituted or substituted with 1, 2 or 3        independently selected R₃ groups;        R₂ is selected from:    -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, -(5- or        6-membered)heteroaryl or -(7- or 10-membered)heteroaryl, each of        which is unsubstituted or substituted with 1, 2 or 3        independently selected R₆ groups;        each R₃ is independently selected from:    -   (a) -halo, —CN, —NO₂; or    -   (b) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (c) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (d) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (e) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (f) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, each        of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₅ groups; or    -   (g) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        a is an integer selected from 1, 2 or 3;        Y is selected from O, S, or NT₃;        the 6-membered ring denoted as Q₁ is selected from        —(C₆)cycloalkyl, —(C₆)cycloalkenyl, -(6-membered)heterocycle,        -phenyl, or -(6-membered)heteroaryl;        n is an integer selected from 0, 1, 2 or 3;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which        is unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In one embodiment, the present invention relates to a compound havingthe following general formula (V.1):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃; or    -   (d) —C(═O)T₃; or    -   (e) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃;        or    -   (f) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃; or    -   (g) —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,        —(C₁-C₄)alkoxy, each of which is unsubstituted or substituted        with 1 or 2 independently selected R₅ groups;        each R₂ is independently selected from:    -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃; or    -   (d) —C(═O)T₃; or    -   (e) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃;        or    -   (f) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃; or    -   (g) —(C₁-C₅)alkyl, —(C₂-C₅)alkenyl, —(C₂-C₅)alkynyl,        —(C₁-C₅)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1 or 2 independently selected R₅ groups;    -   wherein both R₂ can together form a (2- to 6-membered)bridge,        which is unsubstituted or substituted with 1 or 2 independently        selected R₅ groups;        the 6-membered ring denoted as Q₁ is selected from        -(6-membered)heterocycle, or -(6-membered)heteroaryl, each of        each at least containing one nitrogen atom at the position as        depicted in formula (V.1);        Q₂ is selected from fused benzo or 6-membered heteroaryl, each        of which is unsubstituted or substituted with 1 or 2        independently selected R₆ groups;        E₁ is selected from C(T₃)₂, or NT₃;        the dashed line in the 5-membered ring denotes the presence or        absence of a bond, wherein E₂ is selected from C(T₃)₂, NT₃ if        the bond is absent, and E₂ is selected from CT₃, or N if the        bond is present;        Y is selected from O, S, or NT₃;        a is an integer selected from 1, 2 or 3;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₁, T₂, and T₃ is independently is independently —H or        —(C₁-C₅)alkyl which is unsubstituted or substituted with 1 or 2        independently selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In one embodiment, the present invention relates to a compound havingthe following general formula (V.2):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from —H; —OT₃, —N(T₃)₂, —ST₃, —(C₁-C₃)alkoxy or—(C₁-C₃)alkyl, wherein T₃ is selected from —H or —(C₁-C₂)alkyl;a is an integer selected from 1, 2 or 3;each E₃ is independently selected from O or S;each R₆ is independently selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl,—(C₂)alkynyl, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo,—N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or—S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (V.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is —(O—C₃)alkyl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (V.2) or a pharmaceutically acceptablederivative thereof, wherein a=2.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (V.2) or a pharmaceutically acceptablederivative thereof, wherein E₃ is O.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (V.2) or a pharmaceutically acceptablederivative thereof, wherein R₆ is —H; —OH, —Cl, —OCH₃, —SH, —SCH₃ or—CH₃.

In one embodiment, the present invention relates to a compound havingthe following general formula (VI):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, -(5- or        6-membered)heteroaryl or -(7- or 10-membered)heteroaryl, each of        which is unsubstituted or substituted with 1, 2 or 3        independently selected R₆ groups;        each R₂ is independently selected from:    -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (d) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (f) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (g) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;    -   wherein both R₂ can together form a (2- to 6-membered)bridge,        which is unsubstituted or substituted with 1 or 2 independently        selected R₅ groups;        R₃ is selected from ═O, ═NT₃, —S, —OT₃, —OC(═O)T₃,        —OC(═O)N(T₁)(T₂), —OC(═O)OT₃, —ST₃, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂), —S(═O)OT₃, —S(═O)N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, or —N(T₃)S(═O)N(T₁)(T₂);        R₄ is selected from:    -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, -(5- or        6-membered)heteroaryl or -(7- or 10-membered)heteroaryl, each of        which is unsubstituted or substituted with 1, 2 or 3        independently selected R₆ groups;        E₁ is selected from C(T₃)₂, O, S or NT₃;        a is an integer selected from 0, 1, 2, or 3;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, —S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which        is unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (VI.1):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl, or -(6-membered)heteroaryl, each of whichis unsubstituted or substituted with 1 or 2 independently selected R₆groups;Y is selected from O or S;each R₂ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃; or    -   (d) —C(═O)T₃; or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃; or    -   (f) —(C₁-C₅)alkyl, —(C₂-C₅)alkenyl, —(C₂-C₅)alkynyl,        —(C₁-C₅)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1 or 2 independently selected R₅ groups;    -   wherein both R₂ can together form a (2- to 6-membered)bridge,        which is unsubstituted or substituted with 1 or 2 independently        selected R₅ groups;        R₄ is selected from -phenyl, or -(6-membered)heteroaryl, each of        which is unsubstituted or substituted with 1 or 2 independently        selected R₆ groups;        E₁ is selected from CT₃, or N;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃;        each T₃ is independently —H or —(C₁-C₅)alkyl which is        unsubstituted or substituted with 1 or 2 independently selected        R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (VI.2):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl or -heteroaryl selected from the groupconsisting of pyridine, pyrazine, pyridazine and pyrimidine, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;a is an integer selected from 0, 1 or 2;

E₂ is O or S;

T₃ is selected from —H or —CH₃;each R₆ is independently selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl,—(C₂)alkynyl, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo,—N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or—S(═O)₂R₇;each R₇ is independently selected from —H, or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is selected from —H; —OH, —OCH₃, —SH, —SCH₃, —Cl or —CH₃.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is:

wherein R₆ is defined as above.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, wherein a=1.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, wherein E₂ is O.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, wherein R₆ is selected from —H; —OH, —OCH₃, —SH,—SCH₃, —Cl or —CH₃.

In one embodiment, the present invention relates to a compound havingthe following general formula (VII):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from:

-   -   (a) —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, -(5- or        6-membered)heteroaryl or -(7- or 10-membered)heteroaryl, each of        which is unsubstituted or substituted with 1, 2 or 3        independently selected R₆ groups;        R₂ is selected from:    -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (d) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (f) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (g) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicyclo alkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        each R₃ is independently selected from —H, ═O, ═NT₃, ═S, —OT₃,        —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃, —ST₃, —S(═O)T₃,        —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂), —S(═O)OT₃,        —S(═O)N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃,        —N(T₃)C(═O)OT₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃,        —N(T₃)S(═O)₂N(T₁)(T₂), —N(T₃)S(═O)T₃, or —N(T₃)S(═O)N(T₁)(T₂);        R₄ is selected from:    -   (a) —H; or    -   (b) -halo, —CN, —NO₂; or    -   (c) —OT₃, —OC(═O)T₃, —OC(═O)N(T₁)(T₂), —OC(═O)OT₃; or    -   (d) —C(═O)T₃, —C(═O)OT₃, —C(═O)N(T₁)(T₂); or    -   (e) —ST₃, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂OT₃, —S(═O)₂N(T₁)(T₂),        —S(═O)OT₃, —S(═O)N(T₁)(T₂); or    -   (f) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, —N(T₃)S(═O)₂N(T₁)(T₂),        —N(T₃)S(═O)T₃, —N(T₃)S(═O)N(T₁)(T₂); or    -   (g) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₅ groups;        or    -   (h) -phenyl or -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₆ groups;        E₁ is selected from C(T₃)₂, O, S or NT₃;        a is an integer selected from 0, 1, 2, or 3;        b is an integer selected from 0, 1, 2, or 3;        each R₅ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,        -phenyl, —(C₁-C₆)alkylCOOR₇, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₇),        —NR₇(C₁-C₆)alkylCOOR₇, —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈,        —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈, —N(R₇)C(═O)N(R₇)₂,        —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)—C(═O)OR₇, —C(═O)N(R₇)₂,        —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₄)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₇),        —N(R₇)₂, —N(R₇)OH, —N(R₇)S(═O)R₈, —N(R₇)S(═O)₂R₈, —N(R₇)C(═O)R₈,        —N(R₇)C(═O)N(R₇)₂, —N(R₇)C(═O)OR₈, —C(═O)R₇, —C(═O)N(R₇)₂,        —C(═O)OR₇, —OC(═O)R₇, —OC(═O)N(R₇)₂, —OC(═O)OR₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3-        to 6-membered)heterocycle, -(5- to 10-membered)heteroaryl,        —C(halo)₃, —CH(halo)₂, or —CH₂(halo);        each R₈ is independently selected from —H or —(C₁-C₄)alkyl;        each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which        is unsubstituted or substituted with 1, 2 or 3 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (VII.1):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl, or -(6-membered)heteroaryl, each of whichis unsubstituted or substituted with 1 or 2 independently selected R₆groups;R₂ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₅)alkyl, —(C₂-C₅)alkenyl, —(C₂-C₅)alkynyl,        —(C₁-C₅)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1 or 2 independently selected R₅ groups;        each R₃ is independently selected from —H, ═O, ═NT₃, or ═S;        R₄ is selected from:    -   (a) —H; or    -   (b) —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)OT₃,        —N(T₃)C(═O)N(T₁)(T₂); or    -   (c) —OT₃, —OC(═O)T₃; or    -   (d) —C(═O)T₃; or    -   (e) —(C₁-C₅)alkyl, —(C₂-C₅)alkenyl, —(C₂-C₅)alkynyl,        —(C₁-C₅)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, or        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1 or 2 independently selected R₅ groups;        a is an integer selected from 1, 2, or 3;        b is an integer selected from 1, 2, or 3;        each R₅ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —(C₁-C₃)alkylCOOR₇, —OR₇,        —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo,        —N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —S(═O)R₇, or —S(═O)₂R₇;        each R₆ is independently selected from —(C₁-C₃)alkyl,        —(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, —OR₇, —SR₇, —C(halo)₃,        —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,        —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —S(═O)R₇, or        —S(═O)₂R₇;        each R₇ is independently selected from —H, —CH₃, or —CH₂CH₃,        each T₁, T₂, and T₃ is independently —H or —(C₁-C₅)alkyl which        is unsubstituted or substituted with 1 or 2 independently        selected R₅ groups; and        each halo is independently selected from —F, —Cl, —Br, or —I.

In a further embodiment, the present invention relates to a compoundhaving the following general formula (VII.2):

or a pharmaceutically acceptable derivative thereof wherein:R₁ is selected from -phenyl or -heteroaryl selected from the groupconsisting of pyridine, pyrazine, pyridazine and pyrimidine, each ofwhich is unsubstituted or substituted with 1 or 2 independently selectedR₆ groups;R₂ is selected from —(C₁-C₄)alkyl, —(C₂-C₄)alkenyl, —(C₂-C₄)alkynyl,—(C₁-C₄)alkoxy, each of which is unsubstituted or substituted with 1 or2 independently selected R₅ groups;R₄ is selected from —N(T₁)(T₂), —N(T₃)N(T₁)(T₂), —N(T₃)C(═O)T₃, or—N(T₃)C(═O)OT₃;a is an integer selected from 1 or 2;b is an integer selected from 1 or 2;each R₅ is independently selected from —H, —(C₁-C₂)alkyl, —(C₂)alkenyl,—(C₂)alkynyl, —OR₇, —SR₇, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo,—N₃, —NO₂, —N(R₇)₂, —N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or—S(═O)₂R₇;each R₆ is independently selected from —C(halo)₃, —CH(halo)₂,—CH₂(halo), or -halo;each R₇ is independently selected from —H, or —CH₃; andeach T₁, T₂, and T₃ is independently selected from —H or —CH₃; andeach halo is independently selected from —F, —Cl, —Br, or —I.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is -phenyl, which is unsubstituted orsubstituted with 1 or 2 independently selected R₆ groups.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein R₁ is -phenyl, which is unsubstituted orsubstituted with 1 or 2 independently selected groups selected from—C(Cl)₃, —CH(Cl)₂, —CH₂(Cl), or —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein

wherein R₆ is selected from —H, —C(Cl)₃, —CH(Cl)₂, —CH₂(Cl), or —Cl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein R₂ is —(C₁-C₄)alkyl.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein R₄ is —N(T₁)(T₂), wherein each T₁, and T₂ isindependently selected from —H or —CH₃

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein a=1 and b=1.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, wherein halo is Cl.

Exemplified Compounds

In an optional embodiment, the present invention relates to thecompounds depicted in Table 1 or a pharmaceutically acceptablederivative thereof.

TABLE 1 Com- pound Chemical structure I.3

II.3

III.3

IV.3

V.3

VI.3

VII.3

In an optional embodiment, the present invention relates to a compoundhaving the general formula (I.2) or a pharmaceutically acceptablederivative thereof, where Compound (I.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (II.2) or a pharmaceutically acceptablederivative thereof, where Compound (II.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (III.2) or a pharmaceutically acceptablederivative thereof, where Compound (III.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (IV.2) or a pharmaceutically acceptablederivative thereof, where Compound (IV.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (V.2) or a pharmaceutically acceptablederivative thereof, where Compound (V.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VI.2) or a pharmaceutically acceptablederivative thereof, where Compound (VI.3) is excluded.

In an optional embodiment, the present invention relates to a compoundhaving the general formula (VII.2) or a pharmaceutically acceptablederivative thereof, where Compound (VII.3) is excluded.

DEFINITIONS

As used in connection with the Compounds herein, the terms used hereinhaving following meaning:

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, a first group is substituted with up to three secondgroups. In another embodiment, a first group is substituted with one ortwo second groups. In another embodiment, a first group is substitutedwith only one second group.

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Abranched alkyl means that one or more straight chain —(C₁-C₈)alkylgroups, such as methyl, ethyl or propyl, replace one or both hydrogensin a —CH₂— group of a straight chain alkyl. A branched non-cyclichydrocarbon means that one or more straight chain —(C₁-C₁₀)alkyl groups,such as methyl, ethyl or propyl, replace one or both hydrogens in a—CH₂— group of a straight chain non-cyclic hydrocarbon. Representativebranched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl, -iso-butyl,-tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₁-C₃)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 3 carbon atoms. Representative straightchain —(C₁-C₃)alkyls include -methyl, -ethyl, and -n-propyl.Representative branched —(C₁-C₃)alkyls include -iso-propyl.

“—(C₁-C₂)alkyl” means a straight chain non-cyclic hydrocarbon having 1or 2 carbon atoms. Representative straight chain —(C₁-C₂)alkyls include-methyl and -ethyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. A branched alkenyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— or —CH═ group of a straightchain alkenyl. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl, and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl, and the like.

“—(C₂-C₄)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 4 carbon atoms and including at least onecarbon-carbon double bond. Representative (C₂-C₄)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, and the like.

“—(C₂-C₃)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 3 carbon atoms and including at least onecarbon-carbon double bond. Representative (C₂-C₃)alkenyls include-vinyl, -allyl, and the like.

“—(C₂)alkenyl” means a straight chain non-cyclic hydrocarbon having 2carbon atoms and including one carbon-carbon double bond.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. A branched alkynyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— group of a straight chainalkynyl. Representative straight chain and branched —(C₂-C₁₀)alkynylsinclude -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl,-2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl,-5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl,-2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl,-2-decynyl, -9-decynyl, and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl, and the like.

“—(C₂-C₄)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 4 carbon atoms and including at least onecarbon-carbon triple bond. Representative (C₂-C₄)alkynyls include-acetylenyl, -propynyl, -1-butynyl, -2-butynyl, and the like.

“—(C₂-C₃)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 3 carbon atoms and including at least onecarbon-carbon triple bond. Representative (C₂-C₃)alkynyls include-acetylenyl, -propynyl, and the like.

“—(C₂)alkynyl” means a straight chain non-cyclic hydrocarbon having 2carbon atoms and including one carbon-carbon triple bond.

“—(C₁-C₆)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and from 1 to 6 carbonatoms. Representative straight chain and branched (C₁-C₆)alkoxys include-methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, -5-methoxypentyl,3-ethoxybutyl and the like.

“—(C₁-C₄)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and from 1 to 4 carbonatoms. Representative (C₁-C₄)alkoxys include -methoxy, -ethoxy,methoxymethyl, 2-methoxyethyl, and the like.

“—(C₁-C₃)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and from 1 to 3 carbonatoms. Representative (C₁-C₃)alkoxys include -methoxy, -ethoxy,methoxymethyl, 2-methoxyethyl, and the like.

“—(C₃-C₁₄)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 14 carbon atoms. Representative (C₃-C₁₄)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl,and -cyclotetradecyl.

“—(C₃-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms. Representative (C₃-C₁₂)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl.

“—(C₆-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 6 to 12 carbon atoms. Representative (C₆-C₁₂)cycloalkyls are-cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl,cycloundecyl, and -cyclododecyl.

“—(C₄-C₈)cycloalkyl” or “4- to 8-member cycloalkyl ring” means asaturated monocyclic hydrocarbon having from 4 to 8 carbon atoms.Representative —(C₄-C₈)cycloalkyls are -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, and -cyclooctyl.

“—(C₃-C₈)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₃-C₇)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms. Representative (C₃-C₇)cycloalkyls includecyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and -cycloheptyl.

“—(C₆-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 6 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₆-C₁₄)bicycloalkyls include -indanyl, -norbornyl,-1,2,3,4-tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl,-perhydronaphthalenyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl, bicyclo[3.2.1]octyl,bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl,bicyclo[4.2.2]decyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.1]decyl, and thelike.

“—(C₈-C₂₀)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 20 carbon atoms and at least one saturated cyclic alkylring. Representative —(C₈-C₂₀)tricycloalkyls include -pyrenyl,-adamantyl, noradamantyl, -1,2,3,4-tetrahydroanthracenyl,-perhydroanthracenyl -aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl,-5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl,tetradecahydro-1H-cyclohepta[a]naphthalenyl,tetradecahydro-1H-cycloocta[e]indenyl,tetradecahydro-1H-cyclohepta[e]azulenyl,hexadecahydrocycloocta[b]naphthalenyl,hexadecahydrocyclohepta[a]heptalenyl, tricyclo-pentadecanyl,tricyclo-octadecanyl, tricyclo-nonadecanyl, tricyclo-icosanyl, and thelike.

“—(C₃-C₁₄)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 3to 14 carbon atoms. Representative (C₃-C₁₄)cycloalkenyls include-cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl,-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl,-cyclodecadienyl, -cyclotetradecenyl, -cyclododecadienyl, and the like.

“—(C₅-C₁₄)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 14 carbon atoms. Representative (C₅-C₁₄)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl,-cyclododecadienyl, and the like.

“—(C₆-C₁₂)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 6to 12 carbon atoms. Representative (C₆-C₁₂)cycloalkenyls include-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl,-cyclodecadienyl, -cyclododecadienyl, and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, and the like.

“—(C₇-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 7 to14 carbon atoms. Representative —(C₇-C₁₄)bicycloalkenyls include-bicyclo[3.2.0]hept-2-enyl, -indenyl, -pentalenyl, -naphthalenyl,-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, norbornenyl,and the like.

“—(C₈-C₂₀)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to20 carbon atoms. Representative —(C₈-C₂₀)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl,2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl,2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl,8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl,1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,c]cyclononenyl, andthe like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3-to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, a 5-membered heterocycle can contain up to4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatoms,and a 7-membered heterocycle can contain up to 5 heteroatoms. Eachheteroatom is independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(3- to 7-membered)heterocycle can be attached via a nitrogen or carbonatom. Representative -(3- to 7-membered)heterocycles include pyridyl,furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl,thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl,dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“-(5- or 6-membered)heterocycle” or “-(5- or 6-membered)heterocyclo”means a 5- or 6-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 5-memberedheterocycle can contain up to 4 heteroatoms and a 6-membered heterocyclecan contain up to 4 heteroatoms. Each heteroatom is independentlyselected from nitrogen, which can be quaternized; oxygen; and sulfur,including sulfoxide and sulfone. The -(5- or 6-membered)heterocycle canbe attached via a nitrogen or carbon atom. Representative -(5- or6-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl,oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl,valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrazolyl, and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3-to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, and a 5-membered heterocycle can contain upto 4 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(3- to 5-membered)heterocycle can beattached via a nitrogen or carbon atom. Representative -(3- to5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl,imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl and the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl, -indolinyl, -isoindolinyl,-1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl,pyrrolopyrrolyl and the like.

“—(C₃-C₁₂)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₁₂)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl, -oxocanyl, -1,5-dioxocanyl,-1,3,5-trioxocanyl, -oxonanyl, -1,5-dioxonanyl, -1,4,7-trioxonanyl,-oxacyclododecanyl, -1,7-dioxacyclododecanyl, and-1,5,9-trioxacyclododecanyl.

“—(C₃-C₇)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₇)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur, orat least two carbon atoms of one or both of the rings are replaced witha heteroatom independently selected from nitrogen, oxygen, and sulfur.In one embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members where at least one carbon atom is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- or 6-membered)heteroaryl's ring containsat least one carbon atom. Representative -(5- or 6-membered)heteroarylsinclude pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCl, —CHClI, and—CHI.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —Cl₃.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“Oxo”, “═O”, and the like as used herein mean an oxygen atom doublybonded to carbon or another element.

“Thiooxo”, “thioxo”, “═S”, and the like as used herein mean a sulfuratom doubly bonded to carbon or another element.

“Imino”, “═NT₃”, and the like as used herein mean a nitrogen atom doublybonded to carbon or another element.

As used herein in connection with Formula (I), when the dashed line inthe 6-membered ring that is fused to the Q group is absent, then Formula(I) is understood to appear as follows

i.e., the 6-membered ring that is fused to the Q group contains nodouble bond between the ring-carbon to which the R₃ group is attachedand the adjacent carbon atom to which the R₄ is attached.

As used herein in connection with Formula (I), when the dashed line inthe 6-membered, nitrogen-containing ring that is fused to the Q groupindicates the presence of a bond, then Formula (I) is understood toappear as follows

i.e., the 6-membered ring that is fused to the Q group contains a doublebond between the ring-carbon to which the R₃ group is attached and theadjacent carbon atom to which the R₄ is attached.

As used herein in connection with Formula (I.1), when the dashed line inthe 6-membered ring that is fused to the Q group is absent, then Formula(I.1) is understood to appear as follows

i.e., the 6-membered ring that is fused to the Q group contains nodouble bond between the ring-carbon to which the R₃ group is attachedand the adjacent carbon atom to which the R₄ is attached.

As used herein in connection with Formula (I.1), when the dashed line inthe 6-membered, nitrogen-containing ring that is fused to the Q groupindicates the presence of a bond, then Formula (I.1) is understood toappear as follows

i.e., the 6-membered ring that is fused to the Q group contains a doublebond between the ring-carbon to which the R₃ group is attached and theadjacent carbon atom to which the R₄ is attached.

As used herein in connection with Formula (II), when the dashed line isabsent, then Formula (II) is understood to appear as follows

i.e., the Formula contains no double bond between the carbon atom towhich the R₂ group and E are attached and the adjacent carbon atom.

As used herein in connection with Formula (II), when the dashed line isabsent, then Formula (II) is understood to appear as follows

i.e., the Formula contains a double bond between the carbon atom towhich the R₂ group and E are attached and the adjacent carbon atom.

“(C₂-C₆)bridge” as used in connection with Formulas (II) and (II.1)means a hydrocarbon chain containing 2 to 6 carbon atoms joining the twocarbon atoms connected to R₄ according to Formulas (II) and (II.1) toform a cyclic ring system. Exemplary compounds of the invention includethose with a (C₂)bridge, —CH₂—CH₂—, joining the two carbon atomsconnected to R₄; a (C₃)bridge, —CH₂—CH₂—CH₂—, joining the two carbonatoms connected to R₄; a (C₄)bridge, —CH₂—CH₂—CH₂—CH₂—, joining the twocarbon atoms connected to R₄; a (C₅)bridge, —CH₂—CH₂—CH₂—CH₂—CH₂—,joining the two carbon atoms connected to R₄; or a (C₆)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, joining the two carbon atoms connected to R₄.Examples of a (C₂-C₆)bridge which optionally contains —HC═CH— within the(C₂-C₆)bridge include —HC═CH—, —CH₂—HC═CH—, —HC═CH—CH₂—,—CH₂—HC═CH—CH₂—, and the like. Examples of a (C₂-C₆)bridge whichoptionally contains —O— within the (C₂-C₆)bridge include —CH₂—O—CH₂—(containing 2 carbon atoms), —CH₂—O—CH₂—CH₂— and —CH₂—CH₂—O—CH₂— (eachcontaining 3 carbon atoms), —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂— and—CH₂—CH₂—CH₂—O—CH₂— (each containing 4 carbon atoms), and the like.

As used herein in connection with Formula (III), when the dashed line isabsent, then Formula (II.1) is understood to appear as follows

i.e., the Formula contains no double bond between the carbon atom towhich the R₂ group and E are attached and the adjacent carbon atom.

As used herein in connection with Formula (II.1), when the dashed lineis absent, then Formula (II.1) is understood to appear as follows

i.e., the Formula contains a double bond between the carbon atom towhich the R₂ group and E are attached and the adjacent carbon atom.

As used herein in connection with Formula (II.2), when the dashed lineis absent, then Formula (II.2) is understood to appear as follows

i.e., the Formula contains no double bond between the carbon atom towhich the nitrogen is attached and the adjacent carbon atom comprised bythe 6-membered ring.

As used herein in connection with Formula (II.2), when the dashed lineis absent, then Formula (II.2) is understood to appear as follows

i.e., the Formula contains a double bond between the carbon atom towhich the nitrogen is attached and the adjacent carbon atom comprised bythe 6-membered ring.

As used herein in connection with Formula (III), when the dashed line isabsent, then Formula (III) is understood to appear as follows

i.e., the Formula contains no double bond between the carbon atom towhich R₁ is attached and the adjacent E₁ group.

As used herein in connection with Formula (III), when the dashed line isabsent, then Formula (III) is understood to appear as follows

i.e., the Formula contains a double bond between the carbon atom towhich R₁ is attached and the adjacent E₁ group.

As used herein in connection with Formula (IV), when the dashed line isabsent, then Formula (IV) is understood to appear as follows

i.e., the Formula contains no double bond between the carbon atom towhich E₁ is attached and the adjacent carbon atom to which R₂ and E₂ areattached.

As used herein in connection with Formula (IV), when the dashed line isabsent, then Formula (IV) is understood to appear as follows

i.e., the Formula contains a double bond between the carbon atom towhich E₁ is attached and the adjacent carbon atom to which R₂ and E₂ areattached.

As used herein in connection with Formula (IV.1), when both dashed linesare absent, then Formula (IV.1) is understood to appear as follows

i.e., the Formula contains no double bond in the 6-membered ringcontaining E₃ and E₄.

As used herein in connection with Formula (IV.1), when one dashed lineis absent, then Formula (IV.1) is understood to appear as follows

i.e., the Formula contains one double bond in the 6-membered ringcontaining E₃ and E₄.

As used herein in connection with Formula (IV.1), when both dashed linesare present, then Formula (IV.1) is understood to appear as follows

i.e., the Formula contains two double bonds in the 6-membered ringcontaining E₃ and E₄.

As used herein in connection with Formula (V.1), when the dashed line isabsent, then Formula (V.1) is understood to appear as follows

i.e., the Formula contains no double bond in the 5-membered ringcontaining E₁ and E₂.

As used herein in connection with Formula (V.1), when the dashed line ispresent, then Formula (V.1) is understood to appear as follows

i.e., the Formula contains a double bond in the 5-membered ringcontaining E₁ and E₂.

The phrase “benzo”, “benzo group” and the like, when used in connectionwith the optionally-substituted Q group in Formulas (I) and (I.1), means

where R₁ and a are defined above for the compounds of Formulas (I) and(IA).

The phrase “(5- or 6-membered)heteroaryl” when used in connection withthe optionally-substituted Q group in Formula (I), means

where at least one carbon atom is replaced with a heteroatomindependently selected from nitrogen, oxygen, and sulfur and R₁ and aare defined above for the compounds of Formula (I). Representative -(5-or 6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.

The phrase “6-membered heteroaryl” when used in connection with theoptionally-substituted Q group in Formula (I.1), means

where at least one carbon atom is replaced with a nitrogen, and R₁ and aare defined above for the compounds of Formula (I.1). Representative6-membered heteroaryls include pyridyl, pyridazinyl, pyrimidyl,pyrazinyl, and the like.

The phrase “pyridine”, “pyridino group” and the like, when used inconnection with the optionally-substituted Q group in Formulas (I) and(IA), means

where R₁ and a are defined above for the Compounds of Formulas (I) and(I.1).

The phrase “pyrimidino”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted Q group in Formulas (I) and(I.1), means

where R₁ and a are defined above for the Compounds of Formulas (I) and(I.1).

The phrase “pyrazino”, “pyrazino group” and the like, when used inconnection with the optionally-substituted Q group in Formulas (I) and(I.1), means

where R₁ and a are defined above for the Compounds of Formulas (I) and(I.1).

The phrase “pyridazino”, “pyridazino group” and the like, when used inconnection with the optionally-substituted Q group in Formulas (I) and(I.1), means

where R₁ and a are defined above for the Compounds of Formulas (I) and(IA).

The phrase “pyridine”, “pyridino group” and the like, when used inconnection with the optionally-substituted R₃ group in Formula (I.2) orwith the optionally-substituted R₁ group in Formula (III.2) or with theoptionally-substituted R₃ group in Formula (IV.2) or with theoptionally-substituted R₁ group in Formula (VI.2) or with theoptionally-substituted R₁ group in Formula (VII.2), means

where R₆ is defined above for the compounds of Formulas (I.2) or (III.2)or (IV.2) or (VI.2) or (VII.2), respectively, and a is an integerselected from 1 or 2.

The phrase “pyrimidine”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted R₃ group in Formula (I.2) orwith the optionally-substituted R₁ group in Formula (III.2) or with theoptionally-substituted R₃ group in Formula (IV.2) or with theoptionally-substituted R₁ group in Formula (VI.2) or with theoptionally-substituted R₁ group in Formula (VII.2), means

where R₆ is defined above for the compounds of Formula (I.2) or (III.2)or (IV.2) or (VI.2) or (VII.2), respectively, and a is an integerselected from 1 or 2.

The phrase “pyrazine”, “pyrazino group” and the like, when used inconnection with the optionally-substituted R₃ group in Formula (I.2) orwith the optionally-substituted R₁ group in Formula (III.2) or with theoptionally-substituted R₃ group in Formula (IV.2) or with theoptionally-substituted R₁ group in Formula (VI.2) or with theoptionally-substituted R₁ group in Formula (VII.2), means

where R₆ is defined above for the compounds of Formula (I.2) or (III.2)or (IV.2) or (VI.2) or (VII.2), respectively, and a is an integerselected from 1 or 2.

The phrase “pyridazine”, “pyridazino group” and the like, when used inconnection with the optionally-substituted R₃ group in Formula (I.2) orwith the optionally-substituted R₁ group in Formula (III.2) or with theoptionally-substituted R₃ group in Formula (IV.2) or with theoptionally-substituted R₁ group in Formula (VI.2) or with theoptionally-substituted R₁ group in Formula (VII.2), means

where R₆ is defined above for the compounds of Formula (I.2) or (III.2)or (IV.2) or (VI.2) or (VII.2), respectively, and a is an integerselected from 1 or 2.

The phrase “(C₆)cycloalkyl” when used in connection with theoptionally-substituted Q₁ group in Formula (V), means

where R₂ is defined above for the compounds of Formula (V).

The phrase “(C₆)cycloalkenyl” when used in connection with theoptionally-substituted Q₁ group in Formula (V), means

where the cyclic non-aromatic hydrocarbon has at least one carbon-carbondouble bond in the cyclic system and where R₂ is defined above for thecompounds of Formula (V).

The phrase “(6-membered)heterocycle” when used in connection with theoptionally-substituted Q₁ group in Formula (V), means

where at least one carbon atom in the ring is replaced with a heteroatomindependently selected from nitrogen, oxygen, and sulfur, and where R₂is defined above for the compounds of Formula (V).

The phrase “(6-membered)heteroaryl” when used in connection with theoptionally-substituted Q₁ group in Formula (V), means

where at least one carbon atom in the ring is replaced with a nitrogen,and where R₂ is defined above for the compounds of Formula (V).

The phrase “(6-membered)heterocycle” when used in connection with theoptionally-substituted Q₁ group in Formula (V.1), means

where at least one further carbon atom in the ring can be replaced witha heteroatom independently selected from nitrogen, oxygen, and sulfur,and where R₂ is defined above for the compounds of Formula (V.1).

The phrase “(6-membered)heteroaryl” when used in connection with theoptionally-substituted Q₁ group in Formula (V.1), means

where at least one further carbon atom in the ring can be replaced witha nitrogen, and where R₂ is defined above for the compounds of Formula(V.1).

The phrase “benzo”, “benzo group” and the like, when used in connectionwith the optionally-substituted Q₂ group in Formula (V.1), means

where R₆ and a are defined above for the compounds of Formula (V.1).

The phrase “(6-membered)heteroaryl” when used in connection with theoptionally-substituted Q₂ group in Formula (V.1), means

where at least one carbon atom is replaced with a nitrogen, and R₆ and aare defined above for the compounds of Formula (V.1). Representative(6-membered)heteroaryls include pyridyl, pyridazinyl, pyrimidyl, andpyrazinyl.

The phrase “pyridine”, “pyridino group” and the like, when used inconnection with the optionally-substituted Q₂ group in Formula (V.1),means

where R₆ and a are defined above for the Compounds of Formula (V.1).

The phrase “pyrimidino”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted Q₂ group in Formula (V.1),means

where R₆ and a are defined above for the Compounds of Formula (V.1).

The phrase “pyrazino”, “pyrazino group” and the like, when used inconnection with the optionally-substituted Q₂ group in Formula (V.1),means

where R₆ and a are defined above for the Compounds of Formula (V.1).

The phrase “pyridazino”, “pyridazino group” and the like, when used inconnection with the optionally-substituted Q₂ group in Formula (V.1),means

where R₆ and a are defined above for the Compounds of Formula (V.1).

“(2- to 6-membered)bridge” as used in connection with Formula (V.1)means a hydrocarbon chain containing 1 to 6 carbon atoms joining the twoatoms of the phenyl ring of Formula (V.1) connected to R₂ to form afused bicyclic ring system. For example, compounds of the invention cancomprise a (C₂-C₆)bridge joining the two positions of the ring.Exemplary compounds of the invention include those with a (C₂)bridge,—CH₂—CH₂—; a (C₃)bridge, —CH₂—CH₂—CH₂—; a (C₄)bridge, —CH₂—CH₂—CH₂—CH₂—;a (C₅)bridge, —CH₂—CH₂—CH₂—CH₂—CH₂—; or a (C₆)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—. Examples of a (2- to 6-membered)bridge whichoptionally contains —O— within the bridge include —O—CH₂—O— (containing1 carbon atom), —CH₂—O—CH₂— (containing 2 carbon atoms), —CH₂—O—CH₂—CH₂—and —CH₂—CH₂—O—CH₂-(each containing 3 carbon atoms),—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—O—CH₂— (eachcontaining 4 carbon atoms), and the like.

“(2- to 6-membered)bridge” as used in connection with Formulas (VI) and(VI.1) means a hydrocarbon chain containing 1 to 6 carbon atoms to forma cyclic ring system connected through just one atom, i.e. the carbonatom connected to R₁ is comprised by the cyclic ring system. Forexample, compounds of the invention can comprise a (C₂-C₆)bridge joiningthe two positions of the ring. Exemplary compounds of the inventioninclude those with a (C₂)bridge, —CH₂—CH₂—; a (C₃)bridge, —CH₂—CH₂—CH₂—;a (C₄)bridge, —CH₂—CH₂—CH₂—CH₂—; a (C₅)bridge, —CH₂—CH₂—CH₂—CH₂—CH₂—; ora (C₆)bridge, —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—. Examples of a (2- to6-membered)bridge which optionally contains a heteroatom selected fromnitrogen, oxygen and sulfur within the bridge include —CH₂—O—CH₂—CH₂—and —CH₂—S—CH₂—CH₂— (each containing 3 carbon atoms),—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂— and—CH₂—CH₂—CH₂—O—CH₂— (each containing 4 carbon atoms), and the like.

The term “animal” includes, but is not limited to, a human or anon-human animal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig.

Preferably, the compounds of the present invention selectively modulatevertebrate TRPM8, more preferably they selectively modulate mammalianTRPM8 and most preferably they selectively modulate human TRPM8.

The phrase “pharmaceutically acceptable derivative”, as used herein,includes any pharmaceutically acceptable salt, solvate, prodrug,radiolabeled, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a compound disclosed herein. In one embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, solvate, radiolabeled, stereoisomer, enantiomer, diastereomer,other stereoisomeric form, racemic mixture, geometric isomer, and/ortautomer, e.g., of a compound disclosed herein. In another embodiment,the pharmaceutically acceptable derivative is a pharmaceuticallyacceptable salt, e.g., of a compound disclosed herein.

The phrase “pharmaceutically acceptable salt”, as used herein, is anypharmaceutically acceptable salt that can be prepared from a compounddisclosed herein including a salt formed from an acid and a basicfunctional group, such as a nitrogen group, of a compound disclosedherein. Illustrative salts include, but are not limited, to sulfate,citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a compound disclosed herein having an acidic functionalgroup, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, cesium, and lithium; hydroxides of alkaline earthmetal such as calcium and magnesium; hydroxides of other metals, such asaluminum and zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; picoline; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines),such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. One skilled in the art will recognize that, e.g., acid additionsalts of a compound disclosed herein can be prepared by reaction of thecompounds with the appropriate acid via a variety of known methods.

A compound disclosed herein can contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. The invention is also meant to encompass all suchpossible forms as well as their racemic and resolved forms or anymixture thereof. When a compound disclosed herein contains an olefinicdouble bond or other center of geometric asymmetry, and unless specifiedotherwise, it is intended to include all “geometric isomers”, e.g., bothE and Z geometric isomers. All “tautomers”, e.g., ketone-enol,amide-imidic acid, lactam-lactim, enamine-imine, amine-imine, andenamine-enimine tautomers, are intended to be encompassed by theinvention as well.

As used herein, the terms “stereoisomer”, “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Optical isomers of a compound disclosed herein can be obtained by knowntechniques such as chiral chromatography or formation of diastereomericsalts from an optically active acid or base.

The phrases “treatment of”, “treating”, and the like include theamelioration or cessation of a condition or a symptom thereof. In oneembodiment, treating includes inhibiting, for example, decreasing theoverall frequency of episodes of a condition or a symptom thereof. Thephrases “prevention of”, “preventing”, and the like include theavoidance of the onset of a condition or a symptom thereof. A “disorder”includes, but is not limited to, the conditions defined above.

The term “half maximal effective concentration” or “EC₅₀” refers to theconcentration of a compound disclosed herein which induces a response ona channel halfway between the baseline and maximum after some specifiedexposure time. The EC₅₀ of a graded dose response curve thereforerepresents the concentration of a compound where 50% of its maximaleffect (which may be either agonistic or antagonistic) on the respectivechannel is observed.

Preparation of the Compounds

The compounds disclosed herein are either commercially available or canbe made using conventional organic synthesis which are known to theperson skilled in the art.

Screening Method

As part of the invention, compound libraries can be employed comprisingcompounds to be tested for having modulating activity for one or moremembers of the transient receptor potential cation channel families. Themethods of the invention can employ such compound libraries e.g. foridentifying suitable modulators of TRPM8 and/or any further member ofthe transient receptor potential cation channel families.

In the context of the present invention, the term “chemical library”means a collection of chemical compounds. A “chemical library” employedin the present invention will comprise at least 2 different compounds,rarely less than about 5 compounds, usually at least about 10 compounds,frequently will have about 50 compounds or more, usually more than about500 compounds such as about 15,000 compounds or more.

The activity of the compounds comprised by such compound libraries onTRPM8 or TRPA 1 (or any further member of the transient receptorpotential cation channel families) can be evaluated in a functional cellbased assay. In such “functional cell based assays” a compound-channelinteraction can lead to a functional response of the cell. Thephysiological response of the cell, initiated by a screening compoundcan be quantified by using recombinant reporter technology. It is knownin the art that the TRP channels are a family of ion channel proteinsthat mediate ion influx of Na⁺ and Ca²⁺ and, in several cases, Mg²⁺. Inthe case of TRPM8, assembly of the channel subunits as tetramers resultsin the formation of cation-selective channels that permeate calciumions. Upon activation, a signal transduction cascade is mediated byTRPM8, producing the perception of cold in the nervous system. Forinstance, the action of menthol on TRPM8 provides the “cool” sensationvia activation of the channel and subsequent increase of intracellularcalcium ions in cells expressing the channel. This calcium influx can beused as read-out in functional cell based assays.

The sequences that encode the members of the transient receptorpotential cation channel families are available to the person skilled inthe art (cf. National Center for Biotechnology Information website:http://www.ncbi.nlm.nih.gov). The methods of amplifying and cloning suchsequences (e.g., by PCR) are also commonly known in the art. Accordingto an optional embodiment, TRPM8 (human) has the nucleic acid or aminoacid sequence as disclosed in GenBank Accession Number NM_(—)024080 orNP_(—)076985.4 and TRPA1 (human) has the nucleic acid or amino acidsequence as disclosed in GenBank Accession Number NM_(—)007332 orNP_(—)015628.2.

Methods of providing suitable test systems are known to the personskilled in the art. For example, a cell based test system can be basedon stably transfected cell lines expressing human TRPM8 or TRPA1.Methods of producing suitable test systems are disclosed, inter alia, inBehrendt H J et al., Br. J. Pharmacol. 2004, 141:737-745, which isenclosed herein by reference. According to an optional embodiment, thefunctional cell based assay utilizes human HEK293 cells recombinantlyexpressing human TRPM8 or TRPA1. Agonistic or antagonistic action of acompound can be quantified via a Ca²⁺-sensitive dye (such as FURA,Fluo-4, etc.), wherein agonists produce an increase of intracellularcalcium ions and antagonists inhibit an increase of intracellularcalcium ions (e.g., triggered by endogenous ligands). Such assays areroutine and well known to the person skilled in the art.

According to an optional embodiment of the present invention, a compoundlibrary comprising suitable compounds is tested in a screening foragonistic and/or antagonistic activity towards TRPM8 and/or otherchannels. Optionally, compounds can be selected as developmentcandidates, which compounds are agonists or partial agonists of TRPM8 incells expressing the channel, but do substantially not exhibit agonistactivity at another channel, such as TRPA1, or at least to a lesserextend. Optionally, the compounds can further be analyzed with regard totheir EC₅₀ values as well as their efficacy values and/or can beanalyzed in a structure-action relationship. Such screening methods areroutine and well known to the person skilled in the art.

According to an embodiment, the present invention further encompassescompounds which are identified in such a screening as developmentcandidates.

EMBODIMENTS OF THE INVENTION

The present invention relates to compounds which are capable ofproducing a cooling sensation when they are brought into contact withthe human body. Such compounds have applications in many fields, forexample in oral and personal hygiene products and foodstuffs, but alsoin cosmetics, pharmaceutical composition products, textile products andpackaging products.

As discussed above, a known compound for producing a sensation of coldis menthol (2-isopropyl-5-methyl-cyclohexanol), which has beenextensively applied as an additive in, for example, foodstuffs and oralhygiene products (see e.g.http://www.leffingwell.com/menthol1/menthinfo.htm; Furrer S M et al.,Chem. Percept. 2008, 1(2):119-126). It is used primarily because itelicits a sensation of coolness in the mouth, and because it has apleasing mint flavour and odour. The cooling effect of menthol is due tothe action of menthol as activating the TRPM8 ligand on sensory/freenerve endings which detect thermal stimuli. Without wishing to be boundby any theory, menthol is believed to activate cold receptors on nerveendings. However, the use of menthol is limited by its strong mintysmell which is undesirable for some applications and its relativevolatility and burning sensations at high concentrations throughunintentional activation of other TRPs/ion channels.

It was found that icilin was capable of producing the same coolingeffect as menthol. Icilin has a number of advantages over menthol, forexample it is more potent, and has a lower acute toxicity, due to itslack of anaesthetic properties. Icilin was considered to be aparticularly useful compound for pharmacological applications because itlacks the flavour and odour of menthol and is not readily absorbedthrough the skin (see e.g. US 2006/0280697 A1 and WO 03/092697 A1).

The compounds and compositions disclosed in the present invention havethe ability to produce a cooling sensation when in contact with the skinand/or mucosal membrane of a human or animal body. The term “coolingsensation”, as used herein, is thus intended to mean any sensation ofcoolness which is perceived by human or animal body. Such a coolingsensation is analogous to the sensation produced by compounds such asmenthol, and/or the sensation elicited when cold-sensitive receptors, inparticular TRPM8, are stimulated.

A cooling sensation is desirable in many different applications. Forexample, the compounds and compositions of the invention haveapplications in a number of products, such as cosmetic productcompositions, food product compositions, textile products,pharmaceutical product compositions and packaging products.

In an embodiment, the present invention relates to a product comprisinga compound that, optionally selectively, modulates the TRPM8 channel(e.g. as evaluated in a functional cell based assay under standardconditions as described herein), and wherein the product is selectedfrom the group consisting of a cosmetic product composition, a foodproduct composition, a textile product, a pharmaceutical productcomposition and a packaging product. It is understood that such productscan comprise any combination of compounds as described herein above, andoptionally can also comprise further cooling agents.

In a further embodiment, the present invention relates to a productcomprising a compound that exhibits selective agonist activity at theTRPM8 channel (e.g. as evaluated in a functional cell based assay understandard conditions as described herein), and wherein the product isselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product.

In a further embodiment, the present invention relates to a productcomprising a compound that acts as a selective TRPM8 agonist or partialagonist (e.g. as evaluated in a functional cell based assay understandard conditions as described herein), and wherein the product isselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product.

In a further embodiment, the present invention relates to a productcomprising an effective amount of a compound that acts as a selectiveTRPM8 agonist or partial agonist (e.g. as evaluated in a functional cellbased assay under standard conditions as described herein), and whereinthe product is selected from the group consisting of a cosmetic productcomposition, a food product composition, a textile product, apharmaceutical product composition and a packaging product.

In a further embodiment, the present invention relates to a productcomprising a compound that exhibits an activity at TRPM8, which activityis at least three times or even at least four times, greater than theactivity of the compound at TRPA1 (e.g. as evaluated in a functionalcell based assay under standard conditions as described herein), andwherein the product is selected from the group consisting of a cosmeticproduct composition, a food product composition, a textile product, apharmaceutical product composition and a packaging product.

In a further embodiment, the present invention relates to a productselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product, which product comprises a compoundselected from the group consisting of Compounds I, II, III, IV, V, VI,VII, I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2, III.2, IV.2,V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, whereinthe Compounds have the chemical structures as defined herein above.

In a further embodiment, the present invention relates to a productselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product, which product comprises a compoundselected from the group consisting of Compounds I.1, II.1, III.1, IV.1,V.1, VI.1, VII.1, I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3,III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have thechemical structures as defined herein above.

In a further embodiment, the present invention relates to a productselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product, which product comprises a compoundselected from the group consisting of Compounds I.2, II.2, III.2, IV.2,V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, whereinthe Compounds have the chemical structures as defined herein above.

In a further embodiment, the present invention relates to a productselected from the group consisting of a cosmetic product composition, afood product composition, a textile product, a pharmaceutical productcomposition and a packaging product, which product comprises a compoundselected from the group consisting of Compounds I.3, II.3, III.3, IV.3,V.3, VI.3, and VII.3, wherein the Compounds have the chemical structuresas defined herein above.

In a further embodiment, the present invention relates to a compoundselected from the group consisting of Compounds I, II, III, IV, V, VI,VII, I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2, III.2, IV.2,V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, whereinthe Compounds have the chemical structures as defined herein above. In afurther embodiment, the present invention relates to a compound selectedfrom the group consisting of Compounds I.1, II.1, III.1, IV.1, V.1,VI.1, VII.1, I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3,IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the chemicalstructures as defined herein above. In a further embodiment, the presentinvention relates to a compound selected from the group consisting ofCompounds I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3,IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the chemicalstructures as defined herein above. In a further embodiment, the presentinvention relates to a compound selected from the group consisting ofCompounds I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3,IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the chemicalstructures as defined herein above. In a further embodiment, the presentinvention relates to a compound selected from the group consisting ofCompounds I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein theCompounds have the chemical structures as defined herein above.

Optionally, the compound exhibits an activity at TRPM8, which activityis at least three times, optionally at least four times, five times,seven times, ten times, 12 times, 15 times or 20 times, greater than theactivity of the compound at TRPA1 (e.g. as evaluated in a functionalcell based assay under standard conditions as described herein).

According to an optional embodiment, the compound acts as a TRPM8partial agonist or agonist (e.g. as evaluated in a functional cell basedassay under standard conditions as described herein). According to anoptional embodiment, the compound acts as a selective TRPM8 partialagonist or agonist (e.g. as evaluated in a functional cell based assayunder standard conditions as described herein).

According to an optional embodiment, the compound acts as a selectiveTRPM8 partial antagonist or antagonist (e.g. as evaluated in afunctional cell based assay under standard conditions as describedherein).

According to a further optional embodiment, in a functional cell basedassay the compound modulates the intracellular calcium level of humancells recombinantly expressing human TRPM8 at least four times, fivetimes, seven times, ten times, 12 times, 15 times or 20 times moreefficient than that of human cells recombinantly expressing human TRPA1(e.g. as evaluated in a functional cell based assay under standardconditions as described herein).

According to an optional embodiment of the present invention, theefficacy value of the compound with regard to TRPM8 (compared to 20 μMmenthol) is greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or 110%(as evaluated in a functional cell based assay under standard conditionsas described herein). According to an optional embodiment of the presentinvention, the EC₅₀ value of the compound with regard to TRPM8(agonistic activity) is less than 20 μM, 15 μM, 12 μM, 10 μM, 8 μM, 6 μMor 4 μM (as evaluated in a functional cell based assay under standardconditions as described herein). According to an optional embodiment ofthe present invention, the EC₅₀ value of the compound with regard toTRPA1 (agonistic activity) is greater than 50 μM, 70 μM, 90 μM, 100 μM,110 μM, 120 μM or 130 μM (as evaluated in a functional cell based assayunder standard conditions as described herein). According to an optionalembodiment of the present invention, the EC₅₀ value of the compound withregard to TRPM8 (agonistic activity) is about 4 times, 5 times, 7 times,10 times, 15 times, 20 times, 25 times or 30 times lower than the EC₅₀value of a compound with regard to TRPA1 (agonistic activity) asevaluated in a functional cell based assay under standard conditions asdescribed herein.

Optionally, the compound is selected from the group consisting ofCompounds I, II, III, IV, V, VI, VII, I.1, II.1, III.1, IV.1, V.1, VI.1,VII.1, I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3,V.3, VI.3, and VII.3, wherein the Compounds have the chemical structuresas defined herein above. Optionally, the compound is selected from thegroup consisting of Compounds I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1,I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3,VI.3, and VII.3, wherein the Compounds have the chemical structures asdefined herein above. Optionally, the compound is selected from thegroup consisting of Compounds I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2,I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds havethe chemical structures as defined herein above. Optionally, thecompound is selected from the group consisting of Compounds I.3, II.3,III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have thechemical structures as defined herein above.

In one further embodiment, the present invention relates to the use of acompound as defined herein above in a product selected from the groupconsisting of a cosmetic product composition, a food productcomposition, a textile product, a pharmaceutical product composition,and a packaging product. In one further embodiment, the presentinvention relates to a compound as defined herein above for use intherapy. In one further embodiment, the present invention relates to acompound as defined herein above for use in the treatment of pain. Inone further embodiment, the present invention relates to an in vitro useof a compound as defined herein above as cooling agent. In one furtherembodiment, the present invention relates to a cosmetic use of acompound as defined herein above as cooling agent. In one furtherembodiment, the present invention relates to an in vitro method ofmodulating the cold and menthol receptor TRPM8, wherein TRPM8 iscontacted with a compound as defined herein above.

In the context of the present invention, the phrase “effective amount”,when used in connection with a compound of the invention, means anamount effective for: (a) treating or preventing a condition; or (b)detectably activating TRPM8 function in a cell (as evaluated in afunctional cell based assay under standard conditions as describedherein). The terms “modulate”, “modulating”, and the like as used hereinwith respect to TRPM8 or TRPA1 mean the mediation of a pharmacodynamicresponse in a cell from (i) inhibiting or activating the respectivechannel, or (ii) directly or indirectly affecting the normal regulationof the channel activity (e.g., as evaluated in a functional cell basedassay under standard conditions as described herein). Compounds thatmodulate the channel activity include agonists, partial agonists,antagonists, mixed agonists/antagonists, mixed partialagonists/antagonists and compounds which directly or indirectly affectregulation of the channel activity (as evaluated in a functional cellbased assay under standard conditions as described herein).

The terms “selective modulation”, “selectively modulate”, and the likeas used herein with respect to TRPM8 or TRPA1 mean the mediation of apharmacodynamic response in a cell from (i) inhibiting or activating therespective channel (in particular, TRPM8) without substantiallytriggering another channel (in particular, TRPA1), or (ii) directly orindirectly affecting the normal regulation of the activity of therespective channel (in particular, TRPM8) without substantiallyaffecting the normal regulation of the activity of another channel (inparticular, TRPA1) (e.g., as evaluated in a functional cell based assayunder standard conditions as described herein).

The terms “selective modulation of TRPM8”, “selectively modulate TRPM8”,and the like as used herein with respect to TRPM8 mean the mediation ofa pharmacodynamic response in a cell from (i) inhibiting or activatingTRPM8 without substantially triggering TRPA1 (or at least to a lesserextend), or (ii) directly or indirectly affecting the normal regulationof the activity of TRPM8 without substantially affecting the normalregulation of the activity of TRPA1 (e.g., as evaluated in a functionalcell based assay under standard conditions as described herein).

As used herein, a compound disclosed herein that binds to a channel andmimics the regulatory effect(s) of an endogenous ligand is defined as an“agonist” (e.g., as evaluated in a functional cell based assay understandard conditions as described herein). As used herein, a compoundthat binds to a channel and is only partly effective as an agonist isdefined as a “partial agonist” (e.g., as evaluated in a functional cellbased assay under standard conditions as described herein). As usedherein, a compound that binds to a channel but produces no regulatoryeffect, but rather blocks binding of another agent to the channel orblocks the functional modulation of the channel by another agent isdefined as an “antagonist” or “silent agonist” (i.e. a compound with noefficacy but binding capacity). For an overview of drug bindingmechanisms see: Ross and Kenakin, Pharmacodynamics: Mechanisms of DrugAction and the Relationship Between Drug Concentration and Effect,Chapter 2 in Goodman & Gilman's The Pharmacological Basis ofTherapeutics 31-32 (J. G. Hardman, L. E. Limbird and A. Goodman-Gilmaneds., 10^(th) ed 2001).

In the context of the present invention, the phrases “selective agonist”or “exhibit selective agonist activity” and the like, when used inconnection with a compound of the invention, mean a compound disclosedherein that binds to a channel (in particular, TRPM8) and mimics theregulatory effect(s) of an endogenous ligand (e.g., as evaluated in afunctional cell based assay under standard conditions as describedherein), but does not substantially activate further channels (inparticular, TRPA1), or at least to a lesser extend.

In the context of the present invention, the phrases “selective TRPM8partial agonist or agonist” or “exhibit selective agonist activity atTRPM8” and the like, when used in connection with a compound of theinvention, means a compound that binds to TRPM8 and mimics theregulatory effect(s) of an endogenous ligand (e.g., as evaluated in afunctional cell based assay under standard conditions as describedherein), but does not substantially activate TRPA1, or at least to alesser extend.

In the context of the present invention, the phrase “antagonist” or“silent agonist”, when used in connection with a compound of theinvention, means a compound according to the invention that binds to achannel (in particular, TRPM8) and produces no regulatory effect, butrather blocks binding of another agent to the channel or blocks thefunctional modulation of the channel by another agent such as anendogenous ligand, e.g., as evaluated in a functional cell based assayunder standard conditions as described herein.

The term “exhibit activity on TRPM8” and the like as used herein withrespect to TRPM8 mean the agonist activity (if the compound acts asagonist) or inhibitory activity (if the compound acts as antagonist) atTRPM8, as can be evaluated in a functional cell based assay understandard conditions as described herein. Optionally, the term “exhibitactivity at TRPM8” and the like as used herein with respect to TRPM8mean the agonist activity at TRPM8, as can be evaluated in a functionalcell based assay under standard conditions as described herein.

As used herein, a functional cell based assay under standard conditionsmeans evaluating the cellular activity of compounds with regard to themodulation of the intracellular calcium level using cells recombinantlyexpressing human TRPM8 or human TRPA1. In particular, in this contextthe term “standard conditions” means an activity test using HEK293 cellsrecombinantly expressing either human TRPM8 or human TRPA1, which cellshave been contacted with a calcium-sensitive dye (such as Fluo-4AM, i.e.Fluo-4-acetoxymethylester), wherein the cells are incubated with thecompound to be tested, and receptor modulation is quantitativelydetected by calcium-dependent changes is fluorescence intensity. Such atest system is disclosed, inter alia, in Behrendt H J et al., Br. J.Pharmacol. 2004, 141:737-745, which is enclosed herein by reference.

According to an optional embodiment, the cosmetic product composition isselected from the group consisting of an insect repellent composition,an oral hygiene composition, a skin care composition, and a hair carecomposition. Personal hygiene applications such as skin carecompositions and hair care compositions include lotions, shaving cream,post shaving preparations, shampoos, conditioners, facial cleansers,soaps, bath oils and foams, antiperspirants, deodorants. Oral hygieneapplications include toothpastes, mouthwashes, dental floss, chewing gumand breath fresheners.

According to an optional embodiment, the food product composition isselected from the group consisting of ice cream, mousse, crème,beverages and confectionery. According to an optional embodiment, thetextile product is selected from the group consisting of shirts,trousers, socks, towels, headgear, underwear and shoes. According to anoptional embodiment, the pharmaceutical product composition is selectedfrom the group consisting of anticancer medicaments, bladder diseasemedicaments and medicaments for the treatment of pain.

It is known in the art that modulators of TRPM8 (including its insectanaloga) can act as insect repellent, can have an activity in thetreatment of tumor (e.g., prostate tumors), can have an activity in thetreatment of inflammatory pain/hyperalgesia, and can act as TRPM8antagonists in the treatment of bladder syndrome or an hyperactivebladder (cf. WO 2010/026094).

Accordingly, the present invention further relates to a compound asdefined herein above for use as insect repellent. The present inventionfurther relates to a compound as defined herein above for use in thetreatment of cancer, in particular prostate cancer. The presentinvention further relates to a compound as defined herein above for usein the treatment of inflammatory pain or hyperalgesia. The presentinvention further relates to a compound as defined herein above for usein the treatment of bladder syndrome or hyperactive bladder.

A cooling sensation can be desirable in packaging products, wherein suchcooling sensation is particularly detected upon contact with the contentof such packaging products (which can comprise different materials suchas paper or plastics). Compounds according to the present invention maybe associated with the packaging product material in various ways, e.g.,by spin coating, printing, micro capsules, direct incorporation into thematerial (e.g. extrusion), covalent binding to molecules of thepackaging material etc. Suitable methods are known to the person skilledin the art.

A cooling sensation can also be desirable in textile products, whereinsuch cooling sensation is particularly detected by wearing suchproducts. Compounds according to the present invention may be associatedwith the textile product material in various ways, e.g., by spincoating, printing, micro capsules, direct incorporation into thematerial (e.g. extrusion), covalent binding to molecules of thepackaging material etc. Suitable methods are known to the person skilledin the art.

The specific nature of the products and compositions of the presentinvention (e.g. the nature of the additional components, the relativeproportions of the components and the physical nature of thecomposition) will depend on the particular application and are known tothe skilled person.

While the above invention has been described with respect to some of itspreferred embodiments, this is in no way to limit the scope of theinvention. The person skilled in the art is clearly aware of furtherembodiments and alterations to the previously described embodiments thatare still within the scope of the present invention.

EXAMPLES

A screening for novel modulators of TRPM8 was conducted. For thescreening, a routine screening setup was used. In particular, thecompounds comprised by a compound library were tested for agonisticactivity towards TRPM8 and a dose response analysis of the mostpromising candidates was conducted (TRPM8 versus TRPA1). In particular,promising candidates were analyzed with regard to their EC₅₀ values aswell as their efficacy values, and 7 development candidates wereselected (i.e. Compounds I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3,as described herein above).

The IUPAC names of the compounds are as follows:

I.3=7-methoxy-2-methyl-3-phenyl-4H-chromen-4-oneII.3=2-{[(2,5-dimethoxyphenyl)amino]methylidene}-5,5-dimethylcyclohexane-1,3-dioneIII.3=3-(5-methylthiophen-2-yl)-N′-[(1E)-pyridin-4-ylmethylidene]-1H-pyrazole-5-carbohydrazideIV.3=N-(2,5-dichlorophenyl)-2-[(6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)sulfanyl]acetamideV.3=1-[4-(2H-1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-(2-methyl-1H-1,3-benzodiazol-1-yl)propan-1-oneVI.3=4-methyl-N-[(4-phenyloxan-4-yl)methyl]benzamideVII.3=[3-(4-chlorophenyl)-4-methylpentyl][3-(dimethylamino)propyl]amine

These compounds are commercially available at, e.g., InterBioScreenLtd.(Moscow, Russia), Vitas-M Laboratory Ltd. (Moskow, Russia) orPrinceton BioMolecular Research. Inc. (Princeton, N.J., USA).

For the above analysis, a functional cell based assay under standardconditions as described herein was used, i.e. the cellular activity ofthe compounds with regard to the modulation of the intracellular calciumlevel was evaluated using cells recombinantly expressing human TRPM8 orhuman TRPA1. In particular, human cells recombinantly expressing eitherhuman TRPM8 or human TRPA1 were used, which cells have been contactedwith a calcium-sensitive dye, wherein the cells were incubated with thecompound to be tested, and receptor modulation was quantitativelydetected by calcium-dependent changes in fluorescence intensity. Such atest system is disclosed, inter alia, in Behrendt H J et al., Br. J.Pharmacol. 2004, 141:737-745, which is enclosed herein by reference.Such a test system is also disclosed, inter alia, in WO 2010/026094,which is also enclosed herein by reference. However, it should beunderstood that any screening method and method suitable for evaluatingthe agonistic activity of compounds towards a channel (such as TRPM8)can be used. Suitable methods are routine and known to the skilledperson.

The dose response analysis of the 7 development candidates are depictedin FIGS. 1-7 and summarized in Table 2.

TABLE 2 EC₅₀ EC₅₀ Efficacy for TRPM8 (TRPM8) (TRPA1) activation (in %)Compound (in μM) (in μM) (compared to 20 μM menthol) I.3 2.01 72.42110.06 II.3 8.01 123.22 46.59 III.3 5.27 113.40 97.65 IV.3 4.12 117.8934.14 V.3 7.53 138.37 70.90 VI.3 8.15 107.64 95.36 VII.3 10.94 56.6245.12

1. A product comprising a Compound I.2 having the following generalformula:

or a pharmaceutically acceptable derivative thereof; wherein: R₁ isselected from —H; —OT₃, —ST₃, or —(C₁-C₃)alkyl, wherein T₃ is selectedfrom —H or —(C₁-C₂)alkyl; R₃ is selected from -phenyl or -heteroarylselected from the group consisting of pyridine, pyrazine, pyridazine andpyrimidine, each of which is unsubstituted or substituted with 1 or 2independently selected R₆ groups; R₄ is selected from —(C₁-C₃)alkyl,—(C₂-C₃)alkenyl, —(C₂-C₃)alkynyl, or —(C₁-C₃)alkoxy; and R₆ is selectedfrom —H, —(C₁-C₂)alkyl, —(C₂)alkenyl, —(C₂)alkynyl, —OR₇, —SR₇,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, -halo, —N₃, —NO₂, —N(R₇)₂,—N(R₇)OH, —C(═O)R₇, —C(═O)OR₇, —S(═O)R₇, or —S(═O)₂R₇; each R₇ isindependently selected from —H, or —CH₃; and each halo is independentlyselected from —F, —Cl, —Br, or —I; and wherein the product is selectedfrom the group consisting of a cosmetic product composition, a foodproduct composition, a textile product, a pharmaceutical productcomposition and a packaging product.
 2. The product of claim 1, whereinthe compound exhibits selective agonist activity at TRPM8.
 3. Theproduct of claim 1, wherein the compound exhibits activity at TRPM8,which activity is at least three times, or even at least four times,greater than the activity of the compound at TRPA1.
 4. The product ofclaim 3, wherein in a functional cell based assay the compound modulatesthe intracellular calcium level of human cells recombinantly expressinghuman TRPM8 at least four times more efficient than that of human cellsrecombinantly expressing human TRPA1.
 5. (canceled)
 6. The product ofclaim 1, wherein the compound is Compound I.3 having the followingchemical structure:


7. (canceled)
 8. The product of claim 1, wherein the cosmetic productcomposition is selected from the group consisting of an insect repellentcomposition, an oral hygiene composition, a skin care composition, and ahair care composition or the food product composition is selected fromthe group consisting of ice cream, mousse, crème, beverages andconfectionery or the textile product is selected from the groupconsisting of shirts, trousers, socks, towels, headgear, underwear andshoes or the pharmaceutical product composition is selected from thegroup consisting of anticancer medicaments, bladder disease medicamentsand medicaments for the treatment of pain. 9-11. (canceled)
 12. A methodof treating a patient comprising administering a compound as defined inclaim 1 to a patient in need thereof.
 13. A method of treating paincomprising administering a compound as defined in claim 1 to a patientin need thereof.
 14. A method of producing a cooling sensation, themethod comprising contacting skin and/or a mucosal membrane of a humanor animal with an effective amount of a compound as defined in claim 1to produce the cooling sensation.
 15. In vitro method of modulating thecold and menthol receptor TRPM8, wherein TRPM8 is contacted with acompound as defined in claim
 1. 16. The product of claim 5, wherein thecosmetic product composition is selected from the group consisting of aninsect repellent composition, an oral hygiene composition, a skin carecomposition, and a hair care composition or the food product compositionis selected from the group consisting of ice cream, mousse, crème,beverages and confectionery or the textile product is selected from thegroup consisting of shirts, trousers, socks, towels, headgear, underwearand shoes or the pharmaceutical product composition is selected from thegroup consisting of anticancer medicaments, bladder disease medicamentsand medicaments for the treatment of pain.
 17. A method of treating apatient comprising administering a compound as defined in claim 5 to apatient in need thereof.
 18. A method of treating pain comprisingadministering a compound as defined in claim 5 to a patient in needthereof.
 19. A method of producing a cooling sensation, the methodcomprising contacting skin and/or a mucosal membrane of a human oranimal with an effective amount of a compound as defined in claim 5 toproduce the cooling sensation.
 20. In vitro method of modulating thecold and menthol receptor TRPM8, wherein TRPM8 is contacted with acompound as defined in claim 5.